Pharmacologic activity and pharmacokinetics of metabolites of regorafenib in preclinical models

Abstract

Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment‐refractory metastatic colorectal cancer. In clinical studies, steady‐state exposure to the M‐2 and M‐5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials. Therefore, we assessed the pharmacokinetics and pharmacodynamics of regorafenib, M‐2, and M‐5 in vitro and in murine xenograft models. M‐2 and M‐5 showed similar kinase inhibition profiles and comparable potency to regorafenib in a competitive binding assay. Inhibition of key target kinases by all three compounds was confirmed in cell‐based assays. In murine xenograft models, oral regorafenib, M‐2, and M‐5 significantly inhibited tumor growth versus controls. Total peak plasma drug concentrations and exposure to M‐2 and M‐5 in mice after repeated oral dosing with regorafenib 10 mg/kg/day were comparable to those in humans. In vitro studies showed high binding of regorafenib, M‐2, and M‐5 to plasma proteins, with unbound fractions of ~0.6%, ~0.9%, and ~0.4%, respectively, in murine plasma and ~0.5%, ~0.2%, and ~0.05%, respectively, in human plasma. Estimated free plasma concentrations of regorafenib and M‐2, but not M‐5, exceeded the IC50 at human and murine VEGFR2, suggesting that regorafenib and M‐2 are the primary contributors to the pharmacologic activity of regorafenib in vivo.

A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies

“…Twenty-seven melanoma lines were examined including 16 harboring BRAFV600 mutations, 10 with NRAS mutations, and one BRAF and NRAS wild-type line. Reg and NU concentrations used correlated to physiologically achievable plasma concentrations (17–19). This approach allowed for analysis of molecule expression levels and changes induced by Reg and NU in melanomas with different mutations.…”

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

“…The potential clinical ramification of the hepatocyte‐hopping phenomenon of RG requires additional investigation. Regorafenib was recently demonstrated to undergo intestinal recirculation, in a manner that may be dependent on bacterial β‐glucuronidase‐mediated deconjugation of RG within the intestinal lumen . Based on these prior insights, it can be surmised that inhibition of Oatp1b2‐mediated transport of RG can diminish hepatocellular accumulation and impaired biliary excretion, and lead to diminished enterohepatic recycling and subsequently result in reduced plasma levels of regorafenib following repeat administration cycles.…”

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients

“…In humans, REG is a CYP3A4 substrate and primarily metabolized in the liver to form two metabolites, a N-oxide derivative and a demethylated N-oxide derivative [25] with similar kinase inhibitory properties [26]. To our knowledge, no data on the CSF distribution of REG and its metabolites have been published so far.…”